This invention relates to the syntheses of swainsonine and analogs thereof.
Swainsonine (1), a potent and specific inhibitor of lysosomal and some of the processing forms of .alpha.-mannosidase [Cenci di Bello et al., Biochem. J. 215, 693 (1983); Tulsiani et al., J. Biol. Chem. 257, 7936 (1982)], may have therapeutic value as an antimetastic [Humpheries et al., Cancer Res. 48, 1410 (1988)], and tumor-proliferative [Dennis, Cancer Res. 46, 5131 (1986)], or immunoregulatory agent [Kino et al., J. Antibiot. 38, 936 (1985)]. Studies on the inhibition of human .alpha.-mannosidase by swainsonine analogs such as 1,4-dideoxy-1,4-imino-D-mannitol (DIM) (2) [Fleet et al., J. Chem. Soc. Chem. Commun. 1984, 1240; Palamarczyk et al., Arch. Biochem. Biophys. 243, 35 (1985); Daniel et al., Glycoconjugate J. 6, 229 (1989)] have recently been reported [Cenci di Bello et al., Biochem. J. 259, 855 (1989)]. N-Alkylation of open chain swainsonine analogues effectively removes all ability to inhibit .alpha.-mannosidase [Al Daher et al., Biochem. J. 258, 613 (1989)]; it is therefore of interest to determine the effect of variation of the size of the six-membered ring of swainsonine on the inhibition of mannosidases. There has been much interest in the synthesis of swainsonine [Bashyal et al., Tetrahedron 43, 3083-3093 (1987); Dener et al., J. Org. Chem. 53, 6022 (1988), and references cited therein], and, in particular, in procedures that could produce significant quantities of material [Bennett et al., J. Am. Chem. Soc. 111, 2580 (1989)].